Influence Mechanism of Polymeric Excipients on Drug Crystallization: Experimental Investigation and Chemical Potential Gradient Model Analysis and Prediction

Abstract

In this work, the influence of temperature, stirring speed, and polymeric excipients on crystal growth kinetics of active pharmaceutical ingredients (APIs) mesalazine and allopurinol was systematically investigated through experimental measurement and chemical potential gradient model. The results indicated that the two-step chemical potential gradient model showed good performance in modeling API crystal growth kinetics within the average relative deviations (ARDs) of 5%. Excipients (poly(ethylene glycol) (PEG), hydroxypropyl methyl cellulose (HPMC), and poly(vinyl pyrrolidone) (PVP)) played a crucial role in inhibiting the API crystal growth in all of the investigated systems. On one hand, excipients improved the API solubility, and on the other hand, the crystal growth rate of APIs was reduced remarkably by excipients. By comparing the diffusion rate constant (k d ) and the surface reaction rate constant (k s ) within the two-step chemical potential gradient model, it was found that the controlling step of mesalazine and allopurinol crystal growth was the surface reaction. Because of the presence of excipients, the diffusion rate constant was markedly decreased and the surface reaction order increased. Excipients hinder the surface reaction and decrease the crystal growth rate. Meanwhile, the crystal growth kinetics of mesalazine and allopurinol were predicted successfully with the ARDs of 2.5 and 6.5% under a certain temperature and stirring speed by the two-step chemical potential gradient model. This work provided a mechanistic understanding of how polymers inhibit API crystal growth.

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations

“…To retain particle size, inhibit crystal growth, prevent agglomeration of precipitated particles, and stabilize a suspension, an excipient, such as a polymer (which provides steric stabilization), a surfactant (which provides electrostatic stabilization), or a combination of both, is added to the suspension [ 56 ]. Additionally, stabilizers can lower the free energy barrier for nucleation by lowering the solution’s surface tension [ 36 , 56 , 57 ].…”

The development of an innovative method to improve the dissolution performance of rivaroxaban

“…Additionally, to increase the viscosity of the coating dispersion, hydroxypropyl cellulose (HPC) was used at a concentration of 2 %. HPC, a cellulose derivative with film-forming properties, acts as a binder and helps to form a protective polymeric film around the cellulose pellets [ 46 ]. Although both HPC and HPMC were considered because both are valuable cellulose derivatives in pharmaceutical formulations and offer film-forming properties, binding capabilities, and solubility-promoting characteristics, the choice between them depended on the specific requirements of the formulation, such as solubility requirements, temperature sensitivity, and desired viscosity [ 47 , 48 ], among other factors.…”